Streptolysin O is one of a group of filterable hemolysins derived from Group A beta-hemolytic streptococci. Specifically, streptolysin O is a 60 kD peptide which is hemolytic in its reduced state but is inactivated upon oxidation. Streptolysin O is used in the art generally as an analytical reagent for permeabilizing cells. See, e.g., Razin et al., Proc. Nat'l. Acad. Sci. (USA), 91:7722-7726 (1994).
U.S. Pat. No. 5,576,289 is directed to methods of treating motor deficit symptoms in diseases such as autism, multiple sclerosis and Tourette's Syndrome by administration of streptolysin O.
U.S. Pat. No. 5,736,508 is directed to methods of treatment of scar tissue including the appearance of fine lines, wrinkles and stretch marks by administration of streptolysin O.
U.S. Pat. No. 5,798,102 is directed to methods of treating symptoms of cardiomyopathy comprising administering a composition comprising beta-amyloid, streptolysin O and growth hormone. U.S. Pat. No. 6,303,127 is similarly directed to methods of treating symptoms of cardiomyopathy in non-human animals, Parkinson's Disease and degenerative liver disease including cirrhosis by administration of a composition comprising beta-amyloid, streptolysin O and growth hormone.
U.S. Pat. No. 6,998,121 is directed to methods of treating connective tissue disorders in animals such as Dupuytren's contracture, scleroderma, Peyronie's disease, mastitis in animals, and claudication due to peripheral arterial disease by the administration of streptolysin O.
U.S. Pat. No. 7,196,058 is directed to methods of alleviating symptoms of reproductive fibrosis conditions in a subject comprising administering effective amounts of streptolysin O. Representative fibroses include uterine fibrosis, fallopian tube fibrosis. The patent also discloses the property by which streptolysin O interacts with the CD44 receptor and inhibits CD44 mediated processes.
U.S. Pat. No. 7,629,312 relates to a method of treatment of connective tissue disorders including tendonitis, claudication resulting from peripheral artery disease, Duputren's contracture, Peyronie's Disease, scleroderma, and connective tissue disorders associated with chronic mastitis by administration of streptolysin O. The patent also discloses the property by which streptolysin O interacts with the CD44 receptor and inhibits CD44 mediated processes.
US 2003/0032614 discloses methods for the treatment of respiratory congestion comprising the administration of a polynucleic acid such as DNA. The publication discloses the treatment of equine heaves by the administration of synthetic DNA. The publication also discloses the sublingual administration of DNA with and without streptolysin O for the treatment of radiation induced mucositis although it was reported that it could not be determined whether the incorporation of streptolysin O improved the therapeutic results.
US 2008/0182789 discloses methods of treating idiopathic pulmonary fibrosis which is a progressive and fatal lung disease characterized by progressive fibrotic changes to the lung tissue. The published application disclosed treatment of a subject diagnosed with idiopathic pulmonary fibrosis with sublingual administration of a composition comprising 2 units of streptolysin and 0.3 μg of salmon testicle DNA. Disease progression was arrested and the subject was observed to have stable or improved results on pulmonary function tests.
US 2010/0144602 discloses methods of inhibiting metastatic cancer by the administration of streptolysin O and further discloses the property by which streptolysin O interacts with the CD44 receptor and inhibits CD44 mediated processes.
U.S. Provisional Application No. 61/486,566, filed May 16, 2011, discloses methods of treating disorders associated with sequestered bacteria such as tuberculosis in subjects comprising the step of administering to the subject a combination therapy comprising streptolysin O and antibiotic therapy. Without being bound by any particular theory of invention it is believed that the streptolysin O promotes treatment of the infection by breaking down the abscesses associated with many pathogenic bacteria allowing the antibiotics to have access to the bacteria within the abscess.
The present invention relates to the discovery that Streptolysin O has bronchodilation effects in addition to its other effects relating to fibrosis such as relate to scar healing, fibrotic diseases and treatment of diseases such as tuberculosis associated with sequestered bacteria.
Bronchodilators are substances that dilate the bronchi and bronchioles and by doing so decrease resistance in the respiratory airway and increase airflow to the lungs. They are useful in diseases such as asthma in which an inflammatory response causes obstruction of airflow and bronchospasm. Symptoms of asthma include wheezing, coughing, chest tightness and shortness of breath. Asthma is a chronic obstructive condition but is not considered a chronic obstructive pulmonary disease as this term is used to specifically refer to combinations of disease that are irreversible such as bronchiectasis, chronic bronchitis and emphysema Self, Timothy. Chrisman, Cary. Finch, Christopher. “Applied Therapeutics: The Clinical Use of Drugs, 9th Edition” Philadelphia: Lippincott Williams & Wilkins, 2009. Chapter 22 (Asthma) Unlike these diseases, the airway obstruction in asthma is usually reversible, but if left untreated, chronic inflammation can lead the lungs to become irreversibly obstructed due to airway remodeling.
Asthma affects the bronchi while emphysema affects the alveoli. Asthma like chronic bronchitis, is a disease of the airways. Obstruction to the flow of air is due to inflammation of the airways as well as spasm of muscles surrounding the airways in asthma. The narrowing that results from spasm of the muscles is called bronchospasm. Generally, bronchospasm in asthma is reversible and subsides spontaneously or with the use of bronchodilators. A major component of asthma is inflammation of the airways, and this inflammation causes thickening of the walls of the airways. This inflammation involves different inflammatory cells and mediators than those seen in chronic bronchitis. This may play a role in the choice of anti-inflammatory medications for these similar yet different entities. In many asthmatics, anti-inflammatory medications such as inhaled steroids are required to reduce this inflammation. In long standing asthma, this chronic inflammation can lead to scarring and fixed airway obstruction.
Bronchodilators can also be useful in the treatment of aspects of other pulmonary diseases including chronic obstructive pulmonary diseases (COPDs) which share the common feature of chronic expiratory airflow limitation i.e., persistent slowing of the rate at which exhalation can be achieved. Common COPDs include chronic bronchitis, emphysema and asbestosis and are characterized by respiratory distress but are not associated with aberrant mucous accumulation. Cigarette smoke is the most common cause of COPDs which are also associated with exposure to respirable dusts particularly in workplace environments of those engaged in occupations such as gold and coal mining, textile manufacturing and cement and steel making.
Bronchodilators are either short-acting or long-acting. Short-acting bronchodilators are used in “rescue” inhalers to provide rapid relief from acute bronchoconstriction. Medications such as salbutamol usually take effect within 20 minutes or less and provide temporary relief from asthma symptoms or flare-ups. Some short-acting β-agonists such as salbutamol are specific to the lungs and can relieve bronchospasms without unwanted cardiac (β-1) side effects of non-specific O agonists such as ephedrine or epinephrine.
Long-acting β2-agonists such as salmeterol and formoterol are useful for preventing bronchoconstriction but are not useful for fast relief. Such medications can relieve airway constriction for up to 12 hours and can be taken twice a day with anti-inflammatory medications.
Other compounds such as anticholinergics, psychostimulant drugs that have an amphetamine like mode of action and theophilline act as bronchodilators but their use is limited because of side effects.
Of interest to the present invention are patents directed to the use of DNA in the absence of gene transfer for treatment of respiratory conditions. U.S. Pat. No. 5,726,160 is directed to a method of method for relieving respiratory congestion in a patient, comprising the step of administering sublingually and in a manner so as not to effect gene transfer and expression, a therapeutically effective amount of DNA in a pharmaceutically acceptable vehicle to a patient having a disease characterized by respiratory congestion, wherein said respiratory congestion is a result of an overproduction of viscous mucus or sputum lodged in said patient's respiratory tract, and wherein said method results in the reduced viscosity of said mucus or said sputum such that there is an increase of production and a reduced accumulation of mucus in said patient's respiratory tract.
U.S. Pat. No. 5,955,442 is directed to methods for treating respiratory disease including cystic fibrosis, emphysema, bronchitis and sinusitis by administration of an effective amount of DNA in a manner so as not to effect gene transfer and expression.
U.S. Pat. No. 5,948,768 is directed to methods of treating otitis media by administration of effective amounts of DNA such as by sublingual administration.
U.S. Pat. No. 6,096,721 is directed to a method for treating mucositis of the respiratory tract in a subject comprising the step of administering DNA to the subject.
U.S. Pat. No. 6,100,244 relates to a method for treating respiratory distress by sublingual administration of DNA. More specifically, the patent provides methods for treating symptoms of respiratory distress not associated with aberrant mucous accumulation in a patient, comprising the step of administering in a manner so as not to effect gene transfer an effective amount of DNA in a pharmaceutically-acceptable vehicle to a patient having a disease characterized by respiratory distress not associated with aberrant mucous accumulation including but not limited to diseases such as chronic obstructive pulmonary disease including bronchitis, emphysema and asbestosis as well as asthma. The patent further provides methods for relieving respiratory congestion in a patient as a result of overproduction of viscous mucus or sputum lodged in the patient's respiratory tract due to conditions including mucositis such as caused by radiation comprising the steps of administering in a manner so as not to effect gene transfer a therapeutically effective amount of DNA in a pharmaceutically-acceptable vehicle to a patient having a disease characterized by respiratory congestion, wherein said respiratory congestion is a result of an overproduction of viscous mucus or sputum lodged in said patient's respiratory tract, and wherein said method results in the reduced viscosity of said mucus or said sputum such that there is an increase of production and a reduced accumulation of mucus in said patient's respiratory tract.
Methods of the invention comprise administration to a patient suffering from respiratory distress an effective amount of DNA. The DNA is preferably provided in an amount ranging from about 0.00012 mg to about 0.003 mg and is preferably formulated in a liquid vehicle and provided at a concentration of approximately 0.0006 mg as single drops. A preferred route of administration is sublingual, but other routes, such as subcutaneous, intravenous, intramuscular, and intrathecal are expected to work. DNA for use in the present invention may be prokaryotic DNA or eukaryotic DNA and may be formulated in a number of pharmaceutically-acceptable vehicles, including water, saline, albumin, and dextrose.
Despite the various therapies known to the art for treating bronchoconstriction there remains a need in the art for improved methods of promoting bronchodilation in subjects in need thereof.